CN101107254A

CN101107254A - Heterocyclic tetracyclic tetrahydrofuran derivatives as 5ht2 inhibitors in the treatment of cns disorders

Info

Publication number: CN101107254A
Application number: CNA2006800032542A
Authority: CN
Inventors: J·M·西德-努纳茨; A·A·H·P·梅根斯; A·A·特拉班科-苏阿雷茨
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2005-01-27
Filing date: 2006-01-25
Publication date: 2008-01-16
Anticipated expiration: 2026-01-25
Also published as: EP1846415A1; EA200701583A1; US20110144094A1; AU2006209397A1; US20080108599A1; EA013595B1; BRPI0607088A2; KR20070098938A; AU2006209397B2; ES2391780T3; CN101107254B; JP4937141B2; EP1846415B1; KR101332218B1; WO2006079637A1; CA2595170A1; NZ556272A; CA2595170C; MX2007009092A; WO2006079637A8

Abstract

This invention concerns novel substituted heterocyclic tetracyclic tetrahydrofuran derivat ives with binding affinities towards serotonin receptors, in particular 5-HT2A and 5- HT2C receptors, and towards dopamine receptors, in particular dopamine D2 receptors and with norepinephrine reuptake inhibition properties, pharmaceutical compositions comprising the compounds according to the invention, the use thereof as a medicine, in particular for the prevention and/or treatment of a range of psychiatric and neurological disorders, in particular certain psychotic, cardiovascular and gastrokinetic disorders and processes for their production. The compounds according to the invention can be represented by general Formula (I) , and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

Description

In the treatment of central nervous system disorders as the heterocycle tetracyclic tetrahydrofuran derivatives of 5HT2 inhibitor

Invention field

The present invention relates to for 5-hydroxytryptamine receptor (5-HT particularly _2AAnd 5-HT _2CAcceptor) and Dopamine Receptors (dopamine D particularly ₂Acceptor) has binding affinity, and heterocycle tetracyclic tetrahydrofuran derivatives with new substituted of norepinephrine reuptake inhibition activity, the pharmaceutical composition that contains The compounds of this invention, it is as the purposes of medicine, particularly as the psychiatry and the neuroscience illness that are used to prevent and/or treat certain limit, the particularly purposes of the medicine of some mental illness, cardiovascular disorder and gastric motility illness, and their preparation method.

Background technology

The WO 97/38991 (Janssen PharmaceuticaN.V.) that announced on October 23rd, 1997 has disclosed the tetracyclic tetrahydrofuran derivatives of the replacement of the therapeutical agent that can be used as treatment or prevention central nervous system (CNS) illness, cardiovascular disorder or disorder of gastrointestinal tract.Especially, described compound exhibits to serotonin 5-HT ₂Acceptor is (particularly to 5-HT _2AAnd 5-HT _2CAcceptor) avidity.

The WO 99/19317 (Janssen Pharmaceutica N.V.) that announced on April 22nd, 1999 has disclosed the tetracyclic tetrahydrofuran derivatives that has the replacement of specific halogen substitute mode on dibenzo azepine , dibenzo plug flat (dibenzooxepine), dibenzo thiepin (dibenzothiepine) or dibenzocycloheptane ring.Described compound can be used for treatment or prevention central nervous system disorders, cardiovascular disorder or disorder of gastrointestinal tract, and demonstrates the compound that discloses than WO 97/38991 and more promptly begin to play a role.

The WO 03/048147 (Janssen PharmaceuticaN.V.) that announces in the WO 03/048146 (Janssen PharmaceuticaN.V.) that on June 12nd, 2003 announced and on June 12nd, 2003 has all disclosed the trans condensed cis 3 by the pure form of precursor preparation stereochemistry of single enantiomer-pure, 3a, 8,12b-tetrahydrochysene-2H-dibenzo [3,4:6,7] ring heptan each method of 4 kinds of diastereomers of [1,2-b] furan derivatives also.

The WO 03/040122 (Janssen PharmaceuticaN.V.) that announced on May 15th, 2003 has disclosed the mandelate of the compound of WO 97/38991 and WO 99/19317.In addition the people finds that surprisingly described salt is more stable than the compound that WO 97/38991 and WO 99/19317 disclose under temperature that improves and relative humidity.

Also will mention the WP 97/39001 (JanssenPharmaceutica N.V.) that announced on October 23rd, 1997 in addition, it has disclosed 5-HT ₂Acceptor demonstrates the different  oxazolidine derivative in heterocycle Fourth Ring of avidity.

Summary of the invention

The purpose of this invention is to provide the novel heterocyclic analogs of the tetracyclic tetrahydrofuran derivatives of WO 97/38991 and WO 99/19317, it is found in for 5-HT _2AAnd 5-HT _2CThe improved avidity aspect of acceptor and norepinephrine reuptake vehicle has the surprised advantage of other people than the former compound.

In addition the people surprisingly, The compounds of this invention has also shown the dopamine D of height to moderate ₂Activity makes described compound be used for the treatment of the illness of dopamine modulating, and particularly the schizophrenia aspect is interesting.None is proved to be performance in the compound of prior art described dopamine D ₂Activity, and how none point out to 5-HT in the prior art document _2AAnd 5-HT _2CAcceptor has introduces described activity in the molecule of avidity, keep 5-HT simultaneously _2AAnd 5-HT _2CThe described avidity of acceptor.

This target is accomplished by novel cpd, its N-oxide form, its pharmaceutically acceptable addition salt or its stereochemistry heterogeneous forms of formula of the present invention (I):

Wherein:

N equals 0,1,2,3,4,5 or 6 integer;

I, j are independently of each other for equaling 0,1,2,3 or 4 integer;

R equals 0,1,2,3 or 4 integer;

R ¹And R ²Be hydrogen separately independently of each other, alkyl carbonyl, alkyl, alkoxyalkyl, alkane carbonyl oxygen base alkyl, alkoxycarbonyl alkyl, aralkyl, aromatic carbonyl, carbalkoxy, aryloxy carbonyl, aralkyl carbonyl, alkoxyl group-carbonyl alkyl carbonyl, list or two (alkyl) aminocarboxyl, single or two (aryl) aminocarboxyl, single or two (aralkyl) aminocarboxyl, list or two (alkoxycarbonyl alkyl) aminocarboxyl, the alkane alkylsulfonyl, arylsulfonyl, aralkyl alkylsulfonyl, list or the amino thiocarbonyl of two (alkyl), list or the amino thiocarbonyl of two (aryl), the single or amino thiocarbonyl of two (aralkyl), single, two or three (alkyl) amidino groups, single, two or three (aryl) amidino groups, and single, two or three (aralkyl) amidino groups; Or R ¹And R ²Can form the group of following formula with the nitrogen-atoms that connects them:

Wherein:

P equals 0,1,2,3 or 4 integer;

Q equals 1 or 2 integer;

M equals 0,1,2 or 3 integer;

Each R ³Be selected from halogen independently of each other, hydroxyl, cyano group, alkyl, alkoxyalkyl, aryloxyalkyl group, list or two (alkyl) aminoalkyl group, hydroxyl carbonylic alkyl, alkoxycarbonyl alkyl, list or two (alkyl) aminocarboxyl alkyl, single or two (aryl) aminocarboxyl alkyl, the single or amino carbonyl oxyalkyl of two (alkyl), the alkyl oxy carbonyl oxygen alkyl, fragrant amino carbonyl oxygen base alkyl, aryl alkyl amino carbonyl oxyalkyl, aryl, alkoxyl group, aryloxy, alkane carbonyl oxygen base, fragrant carbonyl oxygen base, aralkyl carbonyl oxygen base, alkyl carbonyl, aromatic carbonyl, aromatic carbonyl, aryloxy carbonyl, hydroxycarbonyl group, carbalkoxy, list or dialkyl amido, alkyl carbonyl amino, aromatic alkyl carbonyl amino, aromatic carbonyl amino, alkoxycarbonyl amino, amino carbonyl amino, list or two (aralkyl) amino carbonyl amino, alkane alkylsulfonyl alkyl amino-carbonyl amino; Or

Two R ³Group can form divalent group together

-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-1)

-O-CR ⁵R ⁵-CR ⁵R ⁵- (b-2)

-O-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-3)

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵- (b-4)

-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-5)

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-6)

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵- (b-7)

-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O-(b-8) and

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-9)

Wherein, R ⁵Be selected from hydrogen, halogen, hydroxyl, alkoxyl group and alkyl;

R ⁴Be selected from hydrogen, alkyl, aralkyl, alkoxyalkyl, alkane carbonyl oxygen base alkyl, alkoxycarbonyl alkyl, the aromatic carbonyl alkyl, alkylsulfonyloxy alkyl, aryl aryloxycarboxylic, the carbalkoxy aryl, alkyl carbonyl, aromatic alkyl carbonyl, the carbalkoxy alkyl carbonyl, aromatic carbonyl, carbalkoxy, aryloxy carbonyl, aromatic alkoxy carbonyl, single or two (alkyl) aminocarboxyl, list or two (aryl) aminocarboxyl, single or two (aralkyl) aminocarboxyl, single or two (alkoxycarbonyl alkyl) aminocarboxyl, the alkoxyalkyl aminocarboxyl, single, two or three (alkyl) amidino groups, single, two or three (aryl) amidino groups, single, two or three (aralkyl) amidino groups, the alkane alkylsulfonyl, aralkyl alkylsulfonyl, or arylsulfonyl;

Each R ¹⁰Be alkyl or cyano group independently of each other;

A and B are thick and to the aryl or the heteroaryl of center ring separately independently of each other, and be selected from following group: furyl, thienyl, pyrryl,  azoles base, thiazolyl, imidazolyl, different  azoles base, isothiazolyl, the  di azoly, triazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indyl, the indolizine base, isoindolyl, benzofuryl, isobenzofuran-base, benzothienyl, indazolyl, benzimidazolyl-, benzothiazolyl, quinolizinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, chromenyl, naphthyridinyl, and naphthyl, condition is that at least one is one of above-mentioned heteroaryl among A and the B;

Each R ⁹Be selected from hydrogen independently of each other, halogen, cyano group, hydroxyl, carboxyl, nitro, amino, single or two (alkyl) amino, alkyl carbonyl amino, amino-sulfonyl, single or two (alkyl) amino-sulfonyl, alkyl, thiazolinyl, alkoxyl group, alkyl carbonyl and carbalkoxy;

Y represent O, S, S (=O), S (=O) ₂Or NR ⁸

X represents CR ⁶R ⁷, O, S, S (=O), S (=O) ₂Or NR ⁸Wherein

R ⁶And R ⁷Independently be selected from hydrogen, hydroxyl, alkyl and alkoxyl group separately; Or

R ⁶And R ⁷Can form together and be selected from following group: methylene radical (promptly=CH ₂), single or two (cyano group) methylene radical, formula-(CH ₂) ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-,-O-(CH ₂) ₂-O-,-O (CH ₂) ₃The divalent group of O-, or form carbonyl with the carbon atom that connects them;

R ⁸Be selected from hydrogen, alkyl, alkyl carbonyl, aromatic carbonyl, aralkyl, aromatic alkyl carbonyl, alkyl sulphonyl, aryl sulfonyl and aralkyl alkylsulfonyl;

Aryl is a phenyl or naphthyl, and 1,2 or 3 substituting group that randomly is selected from following group separately replaces: halogen, nitro, cyano group, hydroxyl, alkoxyl group or alkyl;

Alkyl represents to have the straight or branched saturated hydrocarbyl of 1 to 10 carbon atom, has the cyclic saturated hydrocarbon base of 3 to 8 carbon atoms, or contains straight or branched part with 1 to 10 carbon atom and the saturated hydrocarbyl with circular part of 3 to 8 carbon atoms; Each group is optional to be replaced by one or more halogens, cyano group, oxo, hydroxyl, formyl radical, carboxyl or amino group;

The ring-type unsaturated alkyl that thiazolinyl is represented to have the straight or branched unsaturated alkyl of 1 to 6 carbon atom or had 3 to 6 carbon atoms; Described group has one or more pairs of keys, and described group is optional by one or more halogens, cyano group, oxo, hydroxyl, formyl radical, and carboxyl or amino group replace; And

Halogen is represented fluorine, chlorine, bromine and iodine.

The invention still further relates to The compounds of this invention as medicine.

The invention still further relates to a kind of pharmaceutical composition, it contains pharmaceutically acceptable carrier or thinner, and as the The compounds of this invention of the treatment significant quantity of activeconstituents.

The invention still further relates to the purposes of the medicine that The compounds of this invention is used to prepare, described medicine passes through 5-HT ₂And D ₂Acceptor and suppress mediation prevention or treatment or the two by norepinephrine reuptake the two haves both at the same time and is used to prevent and/or treat various disease conditions.

Especially, the present invention relates to The compounds of this invention and be used to prepare the purposes that is used for the treatment of and/or prevents the medicine of central nervous system disorders, described central nervous system disorders is anxiety for example, depression and mild depression, bipolar disorder, sleep and sexual dysfunction, psychosis, marginal psychosis, schizophrenia, migraine, personality disorder or obsessive compulsive disorder, social phobia or panic attack, organic mental disorders, the children ' s spirit obstacle is attacked old dysmnesia and posture obstacle, habituation, obesity, Bulimia nerovsa, and similar conditions.

More particularly, the present invention relates to the purposes that The compounds of this invention is used to prepare the medicine of the habituation character that is used to prevent and/or treat anxiety, depression, psychosis, schizophrenia, migraine and drug abuse.

Detailed Description Of The Invention

In preferred embodiments, the present invention relates to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof, wherein R according to general formula (I) ¹And R ²Be hydrogen or alkyl separately independently of each other, each alkyl group is optional to be replaced by hydroxyl, or R ¹And R ²Form formula (a-3) or group (a-5) with the nitrogen-atoms that connects them, wherein m equals 1 or 2 integer.Preferably, alkyl is methyl or ethyl.

In another embodiment preferred, the present invention relates to compound according to general formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof, wherein A and B are aryl or be selected from thienyl and the heteroaryl groups of pyridyl separately independently of each other, and condition is that among A and the B at least one is heteroaryl groups.Preferably, A is a phenyl moiety, and thiophene partly be wherein S 9 or 11 thiophene part.

In another embodiment preferred, the present invention relates to compound, its pharmaceutically acceptable acid or base addition salt according to general formula (I), its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof, wherein X is S, A is a phenyl moiety, B be wherein S 9 or 11 thiophene part.Most preferably, S is at 9.

In another embodiment preferred, the present invention relates to compound according to general formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof, wherein Y is O.

In another embodiment preferred, the present invention relates to compound according to general formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof, wherein Y is CR ⁶R ⁷, O, S, S (=O), S (=O) ₂Or NR ⁸Preferably, CR ⁶R ⁷Be CH ₂Preferably, NR ⁸Be the N-benzyl.

In another embodiment preferred, the present invention relates to compound according to general formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof, wherein:

N equals 1 integer;

I equals 0 integer;

J equals 0 or 1 integer;

R equals 0 integer;

R ¹And R ²Be hydrogen, methyl, ethyl or hydroxyethyl separately independently of each other;

A is a phenyl;

B is thienyl or pyridyl;

R ⁹Be hydrogen;

R ¹⁰Be hydrogen, methylol, methoxycarbonyl or ethoxycarbonyl;

Y is O;

X is CH ₂, S or N-benzyl.

In the application's framework, alkyl is defined as having the unit price straight or branched saturated hydrocarbyl of 1 to 10 carbon atom, for example methyl, ethyl, propyl group, butyl, 1-methyl-propyl, 1,1-dimethyl ethyl, amyl group, hexyl; Alkyl has defined the unit price cyclic saturated hydrocarbon base with 3 to 8 carbon atoms, cyclopropyl for example, methyl cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.The definition of alkyl also is included in the optional alkyl that is replaced by one or more phenyl, halogen, cyano group, oxo, hydroxyl, formyl radical and amino group on one or more carbon atoms; hydroxyalkyl for example; particularly methylol and hydroxyethyl; and multi-haloalkyl, particularly difluoromethyl and trifluoromethyl.

In the application's framework, thiazolinyl is defined as also comprising the alkyl as defined above of one or more pairs of keys, for example vinyl, propenyl, butenyl, pentenyl, hexenyl, cyclopropenyl radical, methylcyclopropene base, cyclobutene base, cyclopentenyl and cyclohexenyl.The definition of thiazolinyl also is included on one or more carbon atoms optional by one or more phenyl, halogen, cyano group, oxo, hydroxyl, formyl radical and the amino thiazolinyl that replaces, for example hydroxy alkenyl, particularly hydroxyalkyl vinyl base.

In the application's framework, halogen generally is meant fluorine, chlorine, bromine and iodine.

In the application's framework, " The compounds of this invention " is meant the compound according to general formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form, and prodrug.

In the application's framework, it is special when relevant compound according to general formula (I) is mentioned, a kind of element comprises all isotropic substances and the mixture of isotopes of this element, no matter be natural existence or synthetic the generation, has natural abundance or isotopic enrichment form no matter be.Especially, when mentioning hydrogen, should understand and be meant ¹H, ²H, ³H and their mixture; When mentioning carbon, be interpreted as being meant ¹¹C, ¹²C, ¹³C, ¹⁴C and their mixture; When mentioning nitrogen, be interpreted as being meant ¹³N, ¹⁴N, ¹⁵N and their mixture; When mentioning oxygen, be interpreted as being meant ¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O and their mixture; And when mentioning fluorine, be interpreted as being meant ¹⁸F, ¹⁹F and their mixture.

Therefore, The compounds of this invention also comprises the compound of one or more isotropic substances with one or more elements and composition thereof, comprise radioactive compound (being also referred to as the compound of labelled with radioisotope), wherein one or more on-radiation atoms are replaced by one of its radio isotope.Term " compound of labelled with radioisotope " is meant the compound according to formula (I) that contains at least one radioactive atom, its N-oxide form, its pharmaceutically acceptable addition salt or its stereochemistry heterogeneous forms.For example, compound can use emission positron or gamma-ray labelled with radioisotope.For radioligand combination technology (membrane receptor mensuration), ³The H atom or ¹²⁵The I atom is selected with substituted atom.For imaging, the most frequently used emission positron (PET) radio isotope is ¹¹C, ¹⁸F, ¹⁵O and ¹³N, all these isotropic substances all produce the transformation period that also had separately 20,100,2 and 10 minutes by accelerator.Because these radioisotopic transformation period are so short, make and only under situation, just can use them with the original position accelerator that produces them, therefore limited their use.The most widely usedly in them be ¹⁸F, ^99mTc, ²⁰¹Tl and ¹²³I.These radioisotopic processing, it is made, separates and mixing in molecule is well known to those skilled in the art.

Especially, described radioactive atom is selected from hydrogen, carbon, nitrogen, sulphur, oxygen and halogen.Preferably, described radioactive atom is selected from hydrogen, carbon and halogen.

Especially, described radio isotope is selected from ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br reaches ⁸²Br.Preferably, described radio isotope is selected from ³H, ¹¹C reaches ¹⁸F.

Pharmacy acceptable salt is defined as comprising the non-toxicity acid salt form of the therapeutic activity that the compound according to general formula (I) can form.Described salt can obtain according to the alkali form of the compound of formula (I) by using suitable acid treatment, described suitable acid for example: mineral acid, for example haloid acid, particularly spirit of salt, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; Organic acid, for example acetate, hydroxyethanoic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexane sulfamic acid, Whitfield's ointment, para-aminosalicylic acid, pamoic acid (pamoicacid) and amygdalic acid.

Conversely, described acid salt form can be converted into free alkali form by using suitable alkaline purification.

The compound according to formula (I) that contains sour proton also can be handled the non-toxic metal or the ammonia additive salt form of the therapeutic activity that is converted into them by using suitable organic bases and mineral alkali.Suitable base salt forms comprises, for example, and ammonium salt, an alkali metal salt and alkaline earth salt, particularly lithium, sodium, potassium, magnesium and calcium salt are with the salt of organic bases, for example, benzathine, N-methyl D-glucosamine, hybramine salt, and with the amino acid salt of arginine and Methionin for example.

Conversely, described salt form can be converted into free form by using suitable acid treatment.

Having defined according to the quaternary ammonium salt of the compound of formula (I) can be by the described compound that forms according to the reaction between the basic nitrogen of the compound of formula (I) and the suitable quaternizing agent, for example optional alkylogen, aryl halide or aralkyl halogen, particularly methyl-iodide and the benzyl iodide that replaces of described quaternizing agent.Also can use other reagent with the good group of leaving away, for example, trifluoromethanesulfonic acid alkyl ester, methylsulfonic acid alkyl ester and alkyl tosylate.Quaternary ammonium salt has positively charged nitrogen.Pharmaceutically acceptable counterion comprises chlorine, bromine, iodine, trifluoroacetic acid root and acetate ion.

The term additive salt that uses in the application's framework also comprises the solvate that can form according to the compound of formula (I) and salt thereof.Described solvate is for example hydrate and alcoholate.

Mean according to the N-oxide form of the compound of formula (I) and to comprise that wherein one or more nitrogen-atoms are oxidized to those formulas (I) compound, particularly wherein one or more uncle's nitrogen (as uncle's nitrogen of piperazinyl or piperidyl) of so-called N-oxide compound by those N-oxide compounds of N-oxidation.The technician need can easily not obtain described N-oxide compound with any creative technology, and because these compounds are meta-bolitess that the picked-up back forms by oxidation in human body, they are the surrogates according to the compound of formula (I) obviously.As is generally known, oxidation is the first step (Textbook of Organic Medicinal andPharmaceutical Chemistry, 1977, the 70-75 pages or leaves) related in the drug metabolism in the ordinary course of things.Also as is generally known, the metabolisable form of compound also can replace compound itself and be applied to the people, has same substantially effect.

The compounds of this invention can have at least one oxidable nitrogen (promptly at R ¹And R ²All be not equal to the tertiary amine part under the situation of H).In the case, probably in the human metabolism, form the N-oxide compound.

According to the program that is used for trivalent nitrogen is converted into its N-oxide form known in the art, the compound of formula (I) can be converted into corresponding N-oxide form.Described N-oxidizing reaction usually can be by making formula (I) parent material and suitable organo-peroxide or inorganic peroxide reaction carry out.Suitable inorganic peroxide comprises, hydrogen peroxide for example, basic metal or alkaline earth metal peroxide (as sodium peroxide, Potassium peroxide); Suitable organo-peroxide can comprise peroxy acid, the peroxidation phenylformic acid (as the 3-chloro peroxide acid) that replaces of peroxidation phenylformic acid or halogen for example, peroxidation paraffinic acid (as peroxidation acetate), alkyl peroxide (as tertbutyl peroxide).Suitable solvent is, for example, and water, low-level chain triacontanol (as ethanol) etc., hydrocarbon (as toluene), ketone (as 2-butanone), halohydrocarbon (as methylene dichloride), and the mixture of these solvents.

Above the term of Shi Yonging " stereochemistry heterogeneous forms " has defined all possible isomeric form that the compound of formula (I) can have.Unless mention in addition or indicate, the chemical name of compound is represented the mixture of all possible stereochemistry heterogeneous forms, and described mixture contains all diastereomers and the enantiomorph of basic molecular structure.More particularly, chiral centre can have R-or S-configuration; Substituting group on the saturated group of bivalent cyclic (part) can have cis or transconfiguration.The compound that comprises two keys can have E or Z stereochemical structure on described pair of key.The stereochemistry heterogeneous forms of the compound of formula (I) obviously will be included in the scope of the present invention.

Abide by the CAS Naming conventions, when two chiral centres of known absolute configuration are present in the molecule, R or S descriptor are given the chiral centre of (based on Cahn-Ingold-Prelog order principle) lowest number-with reference to the center.R ^*And S ^*Separately the expression have undetermined absolute configuration the optical homochiral center.If use " α " and " β ": the highest preferential substituent position on the unsymmetrical carbon in the loop systems with minimum ring numbering is at random always in " α " position of the reference plane (mean plane) that is determined by loop systems.With respect to the highest preferential substituent position on the reference atom, the highest preferential substituent position (according to the hydrogen in the compound of formula (I)) on other unsymmetrical carbons in this loop systems, if be in by the homonymy of the reference plane of this loop systems decision then be named as " α ", perhaps, if it is in the opposite side of the reference plane that is determined by this loop systems then is named as " β ".

Has at least one asymmetric center on the carbon atom of compound in the five-ring that is connected to the alkylamino side chain of formula (I).Described asymmetric center and any other asymmetric centers that exist (as some X group) are indicated by descriptor R and S.

The present invention also comprises the derivative compound (being commonly referred to " prodrug ") of pharmacologically active chemical compounds of the present invention, its degradation in vivo and generate The compounds of this invention.Prodrug (but not always) usually has lower usefulness than its compound that generates of degrading at target acceptor place.When required compound has when making its administration difficulty or chemistry when invalid or physical property, prodrug is useful especially.For example, required compound may be difficult to dissolving, and it may be difficult to pass the mucous epithelium transportation, and perhaps it may have the plasma half-life of the weak point of non-expectation.About the visible Stella of further discussion of prodrug, V.J. etc., " Prodrugs ", Drug Delivery Systems, 1985, the 112-176 pages or leaves, and Drugs, 1985,29,455-473 page or leaf.

The prodrug forms of pharmacologically active chemical compounds of the present invention will be the compound according to formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms and the N-oxide form thereof with esterified or amidated acid groups usually.The acid groups of described esterification comprises formula-COOR ^xGroup, R wherein ^xBe C _1-6One of alkyl, phenyl, benzyl or following group:

Amidated group comprises formula-CONR ^yR ^zGroup, R wherein ^yBe H, C _1-6Alkyl, phenyl or benzyl, R ^zBe-OH, H, C _1-6Alkyl, phenyl or benzyl.Having amino The compounds of this invention can use ketone or aldehyde (as formaldehyde) to derive and form mannich base (Mannich base).This alkali will be hydrolyzed with first order kinetics in the aqueous solution.

Pharmacology

The compounds of this invention particularly according to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of general formula (I), has shown 5-HT ₂Acceptor is especially to 5-HT _2AAnd 5-HT _2CAcceptor is (as D.Hoyer in " Serotonin (5-HT) in neurologic and psychiatric disorders ", M.D.Ferrari edits, and publishes described the name by Boerhaave Commission of the University ofLeiden in 1994) avidity and to D ₂The avidity of acceptor, and have norepinephrine reuptake inhibition activity.The serotonin antagonist properties of The compounds of this invention can by they in " 5-hydroxytryptophan Test on Rats " (be described in Drug Dev.Res., 13, among the 237-244 (1988)) restraining effect and obtain proof.

Compound of the present invention particularly according to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of general formula (I), also has favourable physico-chemical property.For example, they are chemically stable compound.

According to compound of the present invention, particularly according to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of general formula (I), consider they the blocking-up 5-HT ₂Acceptor (is particularly blocked 5-HT _2AAnd 5-HT _2CAcceptor) and D ₂Acceptor, and also influence norepinephrine reuptake and suppress active ability, their useful as drug are used in particular among the preventative and therapeutic treatment of aforementioned these receptor-mediated illnesss.

Therefore, the present invention relates to be used as the compound according to general formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of medicine.

The invention still further relates to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof according to general formula (I) and be used to prepare the purposes of medicine, described medicine is used to prevent and/or treat and passes through 5-HT ₂Acceptor (5-HT particularly _2AAnd 5-HT _2CAcceptor) and D ₂Receptor-mediated, and the illness that suppresses mediation by norepinephrine reuptake.

Consider these pharmacology and physico-chemical property, compound according to general formula (I), its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof can be used as the therapeutical agent that treats and/or prevents following central nervous system disorders: anxiety for example, depression and mild depression, bipolar disorder (comprising two-phase mania and depression), sleep and sexual dysfunction, psychosis, marginal psychosis, schizophrenia, migraine, personality disorder, obsessive compulsive disorder, social phobia, panic attack, attention disorders (comprises the attention deficit Attention Deficit Hyperactivity Disorder, ADHD), organic mental disorders, children ' s spirit obstacle (for example ADHD) is attacked dysmnesia and posture obstacle (particularly the elderly), habituation, obesity, Bulimia nerovsa, and similar conditions.

Especially, The compounds of this invention can be used as antianxiety agent, thymoleptic, antipsychotic drug, antischizophrinic, antimigraine, and the medicine that is used as the potential with the habituation character that overcomes drug abuse.

The compounds of this invention, particularly compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and the prodrug thereof according to general formula (I) also can be used as the therapeutical agent that is used for the treatment of dyskinesia (motoric disorders).It is favourable that The compounds of this invention is united use with the therapeutical agent that is used for the classics of described illness.

The compounds of this invention, particularly compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and the prodrug thereof according to general formula (I) also can be used for treatment or prevents following illness: the neural damage that wound causes, apoplexy, neurodegenerative disease, cognitive disorder (for example dementia and Alzheimer) etc.; Cardiovascular disorder, for example hypertension, thrombosis, apoplexy etc.; And disorder of gastrointestinal tract, gastro-intestinal system mobility dysfunction for example, or the like.

According to such use, the present invention also provides a kind of treatment to suffer from the method for the warm-blooded animal of described disease, described method comprises the The compounds of this invention of whole body drug treatment amount, particularly according to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of general formula (I), effectively treat above-mentioned illness, particularly treat anxiety, psychosis, depression, bipolar disorder (comprising the two-phase depression), the habituation character of migraine and drug abuse.

Therefore, the invention still further relates to The compounds of this invention as medicine, particularly according to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of general formula (I), especially, the compound of formula (I) can be used for the medicine that preparation is used for the treatment of the habituation character of anxiety, psychosis, depression, bipolar disorder (comprising the two-phase depression), migraine and drug abuse.

Experienced personnel in described treatment of diseases can determine the treatment significant quantity of every day from test-results provided below.The treatment significant quantity of every day is extremely about 10mg/kg body weight of about 0.01mg/kg body weight, and more preferably from about the 0.05mg/kg body weight is to about 1mg/kg body weight.

The invention still further relates to a kind of pharmaceutical composition, it comprises pharmaceutically acceptable carrier, and as the The compounds of this invention of the treatment significant quantity of activeconstituents, particularly according to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of formula (I).

According to compound of the present invention, particularly according to compound, its pharmaceutically acceptable acid or base addition salt, its stereochemistry heterogeneous forms, its N-oxide form and prodrug thereof of formula (I), perhaps their any subgroup or combination can be formulated into the various medicament forms that are used for the administration purpose.As suitable composition, can mention all compositions that are generally used for the whole body administration.For preparing pharmaceutical composition of the present invention, with the specific compound of significant quantity, optional additive salt form, as activeconstituents, be incorporated in closely in the mixture with pharmaceutically acceptable carrier, the dosage form required according to administration, described carrier can have many kinds of forms.These pharmaceutical compositions are unit dosage ideally, are applicable to particularly oral administration, rectal administration, percutaneous dosing, parenteral drug administration by injection or pass through inhalation.For example, in the composition of preparation oral dosage form, can use any drug media commonly used, for example, the water that for example uses under the situation of suspension, syrup, elixir, emulsion and solution at oral liquid, glycol, oil, alcohol etc.; The perhaps solid carrier that in pulvis, pill, capsule and tablet, uses, for example starch, sugar, white bole, thinner, lubricant, wedding agent, disintegrating agent etc.Tablet and capsule clearly use solid pharmaceutical carriers in this case because best oral dosage form is represented in administration easily.For the parenteral composition, described carrier generally includes most at least sterilized water, but also can comprise other compositions, for example helps the dissolved composition.But preparation example such as injection liquid, wherein said carrier comprises the mixture of salt brine solution, glucose solution or salt solution and glucose solution.Also the injectable suspension can be prepared, suitable liquid vehicle, suspensoid etc. can be used in this case.Also comprise the solid form preparation that is intended to be converted in the short period of time before use liquid form preparation.In being suitable for the composition of percutaneous dosing, optional penetration enhancers and/or the suitable wetting agent of comprising of described carrier, the additive combination of optional and suitable any character than small proportion, wherein said additive can not bring serious deleterious effect to skin.Described additive can promote to be administered to skin and/or can help to prepare required composition.These compositions can be with the number of ways administration, as through the skin patch, as an agent (spot-on), as ointment.

It is particularly advantageous that aforementioned pharmaceutical composition is formulated as the unit dosage that is easy to administration and dosage homogeneous.Unit dosage used herein is meant the physically separated unit that is suitable for as unitary dose, and constituent parts contains the activeconstituents of the predetermined amount that produces required result of treatment as calculated and required pharmaceutical carrier.The example of these unit dosage is tablet (comprising indentation tablet or coated tablet), capsule, pill, pulvis bag, wafer (wafers), injection liquid or suspension etc., and their many unit dosage forms of separating.

Because The compounds of this invention is the compound of effective Orally-administrable, is particularly advantageous so contain the pharmaceutical composition for oral administration that is used for of described compound.

For the solvability and/or the stability of the compound that improves pharmaceutical composition Chinese style (I), advantageously can use alpha-cylodextrin, beta-cyclodextrin or γ-Huan Hujing or their derivative, the cyclodextrin that replaces of hydroxyalkyl particularly is as the 2-hydroxypropyl-beta-cyclodextrin.Cosolvent such as alcohols also can improve the solvability and/or the stability of The compounds of this invention in the pharmaceutical composition.

Preparation

The compounds of this invention can prepare by consecutive steps usually, and wherein each step all is known for a person skilled in the art.

The compound of the formula for preparing in following method (I) can be synthetic with the form of the racemic mixture of enantiomorph, and described racemic mixture can be separated from each other according to method for splitting known in the art.The racemic compound of formula (I) can be by being converted into corresponding diastereomer salt form with the reaction of suitable chiral acid.Afterwards, for example separate described diastereomer salt form, and discharge described enantiomorph by it by alkali by selectivity or fractional crystallization.The optional mode of the enantiomeric form of separate type (I) compound comprises the liquid phase chromatography of using chiral stationary phase.Described pure stereochemistry heterogeneous forms also can be derived from the pure stereochemistry heterogeneous forms of corresponding suitable starting material, and condition is that described reaction stereospecificity ground takes place.Preferably, specific if desired steric isomer, described compound can be synthetic by the stereospecificity method of preparation.These methods advantageously will be utilized the parent material of enantiomer-pure.

The suitable preparation scheme that is used for The compounds of this invention comprises following scheme:

Option A

Step 1: according to the intermediate compound of formula V and the reagent react of formula (VI).This reaction can known in the artly carry out that (for example this reaction can be carried out in the α position ketone being carried out alkylating method under acidity or the basic reaction conditions by any in organic solvent (for example tetrahydrofuran (THF)), use alkali (for example sodium hydride or N, the N-N-Lithiodiisopropylamide), and use allyl bromide 98) as alkylating agent, generation is according to the intermediate compound of formula (IV), wherein R ⁹, i, j, ring A, ring B and X all have the implication of describing in the above-mentioned final compound according to formula (I).For the compound according to formula (VI), M is suitable alkylated reaction group, for example halogen, hydroxyl or acetoxyl group.

Step 2: usually at room temperature, in the organic solvent of for example tetrahydrofuran (THF) or methyl alcohol, the compound according to formula (IV) is reduced, produce compound according to formula (III) with for example sodium borohydride.

Step 3: for example iodine and sodium bicarbonate react in organic solvent such as acetonitrile or methylene dichloride according to the intermediate compound of formula (III) and cyclizing agent, produce novel intermediate compound according to formula (II), wherein W represents suitable leavings group, preferred halogen, alkyl-or aryl-sulfonyl oxygen, particularly 4-(aminomethyl phenyl) sulfonyloxy or iodine.

Step 4:, use formula HNR by any methods known in the art ¹R ²(R wherein ¹And R ²Suc as formula defining in (I)) amine the intermediate compound according to formula (II) is carried out the N-alkylation, produce novel final compound according to formula (I).For example, described N-alkylation can be easily described in WO 97/38991 in reaction-inert solvent for example methyl alcohol, methyl iso-butyl ketone (MIBK), N, carry out in N-dimethylformamide or the dimethyl sulfoxide (DMSO), and choose wantonly in the presence of suitable alkali and carry out.The temperature that stirs and improve is reflux temperature for example, can improve speed of reaction.Typical reaction conditions is following 8 hours at 130 ℃.

Alternatively, described N-alkylation also can use (J.Med.Chem. (1973), 16 (4), the 403-407 page or leaf) described methods such as Monkovic to carry out, and described method relates to the use of compressive reaction container.

Alternatively, described N-alkylation can also be undertaken by following method: at high temperature for example under 120 ℃, in the compressive reaction vessel in heating at the organic solvent intermediate compound according to formula (II), the formula NHR among the THF for example ¹R ²Amine and alkali (for example calcium oxide).

Use conversion reaction known in the art, the compound of formula (I) can also transform mutually.For example:

A) a kind of compound (R wherein according to formula (I) ¹And R ²Form the group of formula (b) with the nitrogen-atoms that connects them), by handling, can be converted into corresponding primary amines with hydrazine or alkali aqueous solution;

B) a kind of compound (R wherein according to formula (I) ¹Or R ²Be the trifluoromethyl carbonyl), by using the alkali aqueous solution hydrolysis, can be converted into corresponding primary amines or secondary amine;

C) a kind of compound (R wherein according to formula (I) ¹Or R ²For using C _1-6The C that alkyl carbonyl oxy replaces _1-6Alkyl), can be hydrolyzed to wherein R ¹Or R ²Be the C that is replaced by hydroxyl _1-6The compound according to formula (I) of alkyl;

D) a kind of compound (R wherein according to formula (I) ¹And R ²Be hydrogen), can single N-alkylation or two N-alkyl turn to corresponding amine form;

E) a kind of compound (R wherein according to formula (I) ¹And R ²Be hydrogen, or R ¹Or R ²Be hydrogen), can the N-acidylate be corresponding amide;

F) (it contains C to a kind of compound according to formula (I) _1-6Carbalkoxy) can be hydrolyzed to corresponding carboxylic acid;

G) a kind of compound (wherein, R according to formula (I) ⁹Be hydrogen, promptly i and/or j are 0), be under the existence of the butyllithium in the hexane that with an organic solvent (for example tetrahydrofuran (THF)) handled by using for example suitable earboalkoxy chlorine of suitable acylating agent, can be converted into corresponding carbalkoxy compound; Or

H) a kind of compound (R wherein according to formula (I) ⁹Be carbalkoxy), by for example using LiAlH ₄For example reduction in organic solvent (for example tetrahydrofuran (THF)) can be converted into corresponding methylol compound.

The commercially available acquisition of the above-mentioned intermediate compound of mentioning maybe can be abideed by the methods known in the art preparation.For example, the intermediate compound of formula (II) can be according to described method preparation such as Monkovic (J.Med.Chem. (1973), 16 (4), the 403-407 page or leaf).

(wherein X is CH by the intermediate compound of the formula V of following formula (V-a) expression ₂, A is a phenyl, B is a thienyl) and commercially available acquisition, maybe can abide by the methods known in the art preparation.For example, the intermediate compound of formula (V-a) can be according to (Collection of CzechoslovakChemical Communications 1969,34 (2), 468-478) described method preparations such as Protiva.

(wherein X is S by the intermediate compound of the formula V of following formula (V-b) expression, A is a phenyl, and B is a thienyl), can by use appropriate reductant for example aluminum hydride in organic solvent (as tetrahydrofuran (THF)), the intermediate compound according to formula (VI) reduced and prepares.

Option b

Intermediate compound according to formula (VI) can pass through Michal Majchrzak (Journal ofHeterocyclic Chemistry 1985,22 (5), 1203-4; Journal of HeterocyclicChemistry 1985,22 (5) 1205-6) announces that with patent DE2625642 and the described method of PL158223 are prepared.The commercially available acquisition of intermediate compound (wherein X is S, and A is a phenyl, and B is a thienyl) by the formula V of following formula (V-c) expression maybe can be abideed by the methods known in the art preparation.For example, the intermediate compound of formula (V-c) can announce that CS142473, CS217949 and/or the described method of CS200271 are prepared according to patent.

(wherein, X is NR by the intermediate compound of the formula V of following formula (V-d) expression ⁸, A is a phenyl, and B is a pyridyl), can prepare according to the reaction sequence that scheme C shows.

Scheme C

Step 1: according to the compound of formula (VII) with according to the compound of formula (VIII) in for example 200 ℃ of reactions down of high temperature, produce intermediate compound, wherein R according to formula (IX) ¹, R ², R ⁹, i, j have the implication of describing in the above-mentioned final compound according to formula (I).

Step 2: according to the compound of formula (IX) and compound reaction in organic solvent (as N, dinethylformamide) in the presence of alkali (for example sodium hydride) according to formula (X).Alternatively, described reaction can be undertaken by any method that is used for the alkylated benzenes sulfonamide derivatives known in the art.For the compound according to formula (X), X is the proper group of alkylated reaction, for example halogen, hydroxyl or acetoxyl group, and R ⁸Has the implication of describing in the above-mentioned final compound according to formula (I).

Step 3: produced compound according to formula (V-d), wherein R according to the cyclisation of the intermediate compound of formula (XI) ⁸, R ⁹, i, j have the implication of describing in the above-mentioned final compound according to formula (I).Cyclization can by methods known in the art for example Lohse etc. (Tetrahedron Letters, 2001,42,385-389) described method is carried out.

The pure stereochemistry heterogeneous forms of the compound of formula (I) can obtain by using methods known in the art.Diastereomer can for example selective crystallization and chromatographic technique (for example adverse current distributes, liquid chromatography) etc. separate by physical method.

The compound of the formula for preparing in this paper aforesaid method (I) is generally the racemic mixture of enantiomorph, and it can be separated from each other according to method for splitting known in the art.Have the racemic compound of enough alkalescence or tart formula (I) can be separately by being converted into corresponding diastereomer salt form with suitable chiral acid or with suitable chiral base reaction.Subsequently, for example separate described diastereomer salt form, and discharge enantiomorph by it by alkali or acid by selective crystallization or fractional crystallization.The optional mode of the enantiomeric form of separate type (I) compound comprises the liquid phase chromatography of using chiral stationary phase.Described pure stereochemistry heterogeneous forms also can be derived from the pure stereochemistry heterogeneous forms of corresponding suitable starting material, and condition is that described reaction stereospecificity ground takes place.Preferably, specific if desired steric isomer, described compound can be synthetic by the stereospecificity method of preparation.These methods advantageously will be utilized the parent material of enantiomer-pure.

Following examples are intended to the present invention is described and are not to limit the scope of the invention.

Experimental section

Hereinafter, " DCM " is defined as methylene dichloride, and " TNF " is defined as tetrahydrofuran (THF), and " BuLi " is defined as n-Butyl Lithium, and " EtOAc " is defined as ethyl acetate, and " MeOH " is defined as methyl alcohol.

A. the preparation of intermediate compound

Embodiment A 1

A) preparation of intermediate compound 1

At N ₂React under the atmosphere: will be cooled to 0 ℃ in [2,3-b] [l] the benzo thiepin-4 of the thieno-in the dry THF (750ml) (5H)-ketone (0.03998mol) solution, portioning makes an addition to the sodium hydride (0.040mol) of 60% in the mineral oil then.At 0 ℃ of following stirred reaction mixture 45min, at room temperature stirred then 1 hour.Be cooled to after 0 ℃, dropwise making an addition to 3-bromo-l-propylene (0.40mol) mixture in the dry THF (250ml), and make the mixture that obtains reach ambient temperature overnight.Add water, the evaporation organic solvent.Use DCM to extract the enriched material aqueous solution twice, merge organic layer, dry (Na ₂SO ₄), and evaporation organic solvent (vacuum), obtain 10.22g intermediate compound 1.

B) preparation of intermediate compound 2

To be cooled to 0 ℃ in the solution of the intermediate compound 1 (0.03744mol) among the THF (200ml), and portioning adds Sodium Borohydride (0.045mol).Dropwise add MeOH (100ml) after the 10min, reaction mixture is risen to room temperature, and further stirred overnight.Use saturated aqueous ammonium chloride solution cancellation mixture, and evaporation organic solvent (vacuum).Use DCM to extract the enriched material aqueous solution twice, merge organic layer, use salt solution and water to clean, dry then (Na ₂SO ₄).Evaporating solvent (vacuum), and by short open tubular column chromatography purification residue.Collect the product fraction and also evaporate organic solvent, obtain that (isomer mixture: cis/trans 90/10) intermediate compound 2.

C) preparation of intermediate compound 3

At 0 ℃ of N ₂Stir triphenyl phosphine (0.073mol) solution in THF (in right amount) down, add diazene dioctyl phthalate two (1-methylethyl) ester (bis (1-methylethyl) diazenedicarboxylate) (0.071mol), and stirred final suspension 0.5 hour.Dropwise make an addition to the intermediate compound 2 (0.036mol) among the THF (in right amount) and the solution of 4-nitro-phenylformic acid (0.073mol), reaction mixture is risen to room temperature gradually and stirred 16 hours.Evaporating solvent also is dissolved in residue among the DCM, and water and salt solution are cleaned, dry then (Na ₂SO ₄).Evaporating solvent, and by preparative high-performance liquid chromatographic (elutriant: purifying residue EtOAc/ heptane 2/8).Collect pure fraction and evaporating solvent, obtain intermediate compound 3.

D) preparation of intermediate compound 4

At 0 ℃ of mixture that stirs the intermediate compound 3 (0.018mol) in THF (200ml), dropwise make an addition to lithium hydroxide (0.020mol) mixture in the water (50ml) then.Make reaction mixture rise to room temperature 16 hours, and the evaporation organic solvent.Use the DCM cleaning concentrates aqueous solution, separate organic layer, dry (Na ₂SO ₄), evaporating solvent under the pressure that lowers obtains 5.43g intermediate compound 4.

E) intermediate compound 5 and 6 preparation

At room temperature N ₂Under the atmosphere with Tetrafluoroboric acid two (pyridine) iodine (bis (pyridine) iodiniumtetrafluoroborate) (0.0186mol) portioning add in the mixture of intermediate compound 4 (0.0169mol) in DCM (in right amount), and stirred gained solution 1 hour, add sodium thiosulfate solution then.Separate organic layer, dry (Na ₂SO ₄), and under the pressure that lowers evaporating solvent.By preparative high-performance liquid chromatographic purifying residue.Collect the fraction and the evaporating solvent of two kinds of products, obtain 2.5g intermediate compound 5 and 2.1g intermediate compound 6.

B. the preparation of final compound

Embodiment B 1

Final compound 1 (free alkali) and 2 preparation

In the Parr reactor vessel, under 120 ℃ (oil bath temperatures), calorify intermediate compound 5 (0.00127mol), dimethylamine (0.020mol among the THF (10ml), 2M in THF) and the mixture of calcium oxide (0.100g) 8 hours, make reaction mixture be cooled to room temperature then.Filter and remove solid, and the evaporation organic solvent.Use Sep-Pak silicon-dioxide cylinder, the residue (elutriant: DCM/ (MeOH/NH that purifying so obtains in manifold (vacuum) ₃) mixture).Collect product fraction and evaporating solvent, obtain compound 1, i.e. the free alkali of compound 2.By in diethyl ether, handling, residue is converted into oxalate with oxalic acid.Filter final throw out, use cold diethyl ether to clean, and dry, obtain final compound 2 (mixture 80/20 of diastereomer).

Embodiment B 2

The preparation of compound 3

In the Parr reactor vessel, under 120 ℃ (oil bath temperatures), calorify intermediate compound 6 (0.00145mol) among the THF (20ml), the mixture 10 hours of the dimethylamine (0.020mol) of 2M and calcium oxide (0.200g) in THF, make reaction mixture be cooled to room temperature then, and filter and remove solid.The evaporation organic solvent is collected in thus obtained residue among the DCM, and uses saturated NaHCO ₃Solution cleans.Separate organic layer, drying (Na ₂SO ₄), filter and evaporating solvent.Use Sep-Pak silicon-dioxide cylinder purifying oil residues (elutriant: DCM/ (MeOH/NH in manifold (vacuum) ₃)).Collect product fraction and evaporating solvent, obtain final compound 3.

Embodiment B 3

The preparation of final compound 4

At N ₂React under the atmosphere: will be cooled to-78 ℃ in the solution of the final compound 3 (0.00104mol) in the dry THF (15ml), and dropwise make an addition to the BuLi (0.0011mol) of the 1.6M in the hexane then.In-78 ℃ of stirred reaction mixture 35min, and add methylcarbonate (0.003mol).Make the mixture that obtains in 1 hour, rise to room temperature, add water and evaporate organic layer.Thus obtained residue is collected among the DCM, and uses saturated NaHCO ₃The aqueous solution cleans.Separate organic layer, drying (Na ₂SO ₄), filter and evaporating solvent.Use the Sep-Pak silicon-dioxide cylinder residue that purifying obtains in manifold (vacuum).Collect product fraction and evaporating solvent.Be further purified residue by high performance liquid chromatography.Collect the product fraction, and evaporating solvent, final compound 4 obtained.

Embodiment B 4

The preparation of final compound 5

At room temperature N ₂Stir the mixture of the final compound 4 (0.0004mol) in THF (in right amount) under the atmosphere, and add lithium tetrahydroaluminate (0.00044mol), stirred reaction mixture is 2 hours then, and adds saturated aqueous ammonium chloride solution.Separate organic layer, drying (MgSO ₄), filter and evaporating solvent.Use silica gel by short open tubular column chromatography (elutriant: DCM/MeOH 97/3) purifying residue.Collect product level part, and evaporating solvent, the final compound 5 of 0.153g obtained.

Table 1

Table 2

Table 3

The LCMS data that show in the table 4 obtain by the following method:

The HPLC gradient is provided by the HP1100 from Agilent with the post well heater that is set in 40 ℃., divide to light scattering detector (ELSD) then and have simultaneously Waters-Micromass flight time (ToF) mass spectrograph through photodiode array (PDA) detector from the fluid of post in the electron spray ionisation source that positive and negative ionization pattern is operated.

(3.5 μ m carry out reversed-phase HPLC on 4.6 * 30mm), and flow velocity is 1ml/min at the XDB-C18 of Agilent post.Use three moving phase (mobile phase A: 0.5g/1 Spirit of Mindererus, Mobile phase B: acetonitrile, moving phase C: methyl alcohol) to move in following gradient condition: the 6.0min from 80%A, 10%B, 10%C to 50%B and 50%C, at 6.5min to 100%B, maintenance is until 7.0min, and use 80%A, 10%B and 10%C balance again at 7.6min, keep until 9.0min.Use the volume injected of 5 μ L.

By using from 100 to 750 scannings in 1s of the 1s residence time to obtain high resolution mass spectrum.Capillary bobbin electricity volt is 3kV, and the ionizer temperature maintenance is at 140 ℃.Nitrogen is as atomizing gas.From pattern, awl voltage is 30V for positive ionization and negative electricity.Leucine enkephalin (leucine-enkephaline) is for being used to lock the object of reference of spraying.Use Waters-Micromass MassLynx-Openlynx data system to carry out data gathering.All parent peak quality are all corresponding to free alkali+H+.

Table 4

Co. No.	Retention time	Parent peak quality (ES+)	Mw calculates
Co. No.	Retention time	Parent peak quality (ES+)	Mw calculates	14	4.17	318	317
15	4.53	403	402	14	4.17	318	317
15	4.53	403	402	16	4.20/4.25	360	359
17	5.7	416	415	16	4.20/4.25	360	359
17	5.7	416	415	18	4.48	348	347
19	4.32	318	317	18	4.48	348	347
19	4.32	318	317	20	3.52	304	303
2	4.46	318	317	20	3.52	304	303
2	4.46	318	317	21	3.74	304	303

Co. No.	Retention time	Parent peak quality (ES+)	Mw calculates
Co. No.	Retention time	Parent peak quality (ES+)	Mw calculates	34	4.91	390	389
23	4.22/4.41	360	359	34	4.91	390	389
23	4.22/4.41	360	359	27	4.65	387	386
29	4.64	387	386	27	4.65	387	386
29	4.64	387	386	31	3.64	304	303
32	3.63	304	303	31	3.64	304	303
32	3.63	304	303	36	3.40/3.63/3.93/4.01	372	371
5	3.63	348	347	36	3.40/3.63/3.93/4.01	372	371

C. pharmacological examples

Embodiment C .1:5-HT _2AAnd 5-HT _2CThe external binding affinity of acceptor

At compound and the 5-HT of external beam radiotherapy part in conjunction with bounds evaluation (I) in testing _2AAnd 5-HT _2CThe interaction of acceptor.Generally, in buffered substratum (0.2 to 5ml), will cultivate with the sample of organizing goods of enrichment special receptor (1 to 5mg tissue) the radioligand that acceptor has a lower concentration of high binding affinity.In culturing process, radioligand and receptors bind.When reaching binding equilibrium, separate the radioactivity of receptors bind from unconjugated radioactivity, and the activity of receptors bind is counted.In competitive binding experiment, estimate the interaction of test-compound and acceptor.The test-compound of various concentration is added in the culturing mixt that contains goods and radioligand in a organized way.Test-compound will be to suppress combining of radioligand with its binding affinity and the proportional mode of its concentration.Be used for 5-HT _2AThe radioligand of binding affinity is ³The H-Ketanserin ( ³And the employed rat volume cortex that is organized as H-ketanserin).Be used for 5-HT _2CThe radioligand of binding affinity is ³H-mesulergine, and the employed choroid plexus that is organized as pig.

Embodiment C .2 external test NET re-uptake suppresses

Collect rat cerebral cortex and use Ultra-Turrax T25 and the Dual Syrup-homogenizing instrument contains Tris, NaCl and KCl (is respectively 50mM, 120mM and 5mM in the ice refrigerated, pH7.4) carry out homogenate in the homogenate buffer, then, be diluted to the suitable protein concentration of the best that is used for specificity and non-specific binding.Use with the concentration dilution of 20nmol/L the ice refrigerated that contains Tris, NaCl and KCl (be respectively 50mM, 300mM and 5mM, pH 7.4) measure radioligand in the damping fluid [ ³H] Nixosetine (NEN, NET-1084, activity specific～70Ci/mmol) enforcement combination.Then with the 10% DMSO contrast of prepared radioligand (50 μ l) with membrane product (400 μ l) that is diluted to suitable protein concn in advance and 50 μ l, Mazindol (ultimate density 10 ^-6Mol/L) or compound of interest cultivate (60min, 25 ℃) together.By filtering by Packard Filtermate collector to GF/B Unifilter plate, use the ice refrigerated to contain Tris-HCl damping fluid (50mM, 120mM and the 4mM of NaCl and KCl; PH 7.4; 6 * 0.5ml) clean, and detect film in conjunction with activity.Make the dry 24h of strainer, add scintillation solution then.Make the saturated strainer 24h of scintillation solution, on the Topcount scintillometer, count then.Use S-Plus software (Insightful) to calculate specificity in conjunction with percentage ratio and competitive binding curve.

Embodiment C .3: people D _2LThe external binding affinity of acceptor

Melt people's dopamine D _2LThe frozen film of the Chinese hamster ovary celI of acceptor transfection uses the quick homogenate of Ultra-Turrax T25 Syrup-homogenizing instrument, and use contains NaCl, CaCl ₂, MgCl ₂, KCl (respectively do for oneself 50,120,2,1 and 5mM, use HCl to be adjusted to pH 7.7) Tris-HCl measure the suitable protein concn that damping fluid is diluted to the best that is used for specificity and non-specific binding.In measuring damping fluid with the concentration dilution radioligand of 2nmol/L [ ³H] and Spiperone (NEN, activity specific～70Ci/mmol).Use the prepared coating solution of 400 μ l to cultivate prepared radioligand (50 μ l) then, and the 10%DMSO of 50 μ l contrast, butaclamol (Butaclamol, ultimate density 10 ^-6Mol/L) or compound of interest (30min, 37 ℃).Pass through Packard Filtermate collector to GF/B Unifilter plate by filtering, and use ice refrigerated Tris-HCl damping fluid (50mM; PH 7.7; 6 * 0.5ml) clean, and detect film in conjunction with activity.Make the strainer drying, add scintillation solution then, and on the Topcount scintillometer, count.Use S-Plus software (Insightful) to calculate specificity in conjunction with percentage ratio and competitive binding curve.

The result

The said determination result is conduct (pIC in following form ₅₀) value provides: " n.d. " refers to " undetermined ".

Table 5

Co.No.	5-HT _2Λ	5-HT _2C	D ₂	NET-suppresses
Co.No.	5-HT _2Λ	5-HT _2C	D ₂	NET-suppresses	11	8.5	7.4	8.2	5.1
13	8.3	7.0	7.7	＜5	11	8.5	7.4	8.2	5.1
13	8.3	7.0	7.7	＜5	12	7.9	6.6	7.5	＜5
16	7.7	7.8	6.8	5.5	12	7.9	6.6	7.5	＜5
16	7.7	7.8	6.8	5.5	17	7.4	7.0	6.8	＜5
5	n.d.	7.7	6.7	6.4	17	7.4	7.0	6.8	＜5
5	n.d.	7.7	6.7	6.4	25	8.0	8.0	6.7	6.9
10	7.9	7.7	6.7	6.7	25	8.0	8.0	6.7	6.9
10	7.9	7.7	6.7	6.7	2	＞8	8.1	6.7	7.2
15	6.7	6.6	6.6	5.6	2	＞8	8.1	6.7	7.2
15	6.7	6.6	6.6	5.6	23	＞8	8.4	6.6	5.5
27	n.d.	7.3	6.4	＜5	23	＞8	8.4	6.6	5.5
27	n.d.	7.3	6.4	＜5	9	7.8	7.6	6.4	6.5
21	＞8	8.4	6.3	6.9	9	7.8	7.6	6.4	6.5
21	＞8	8.4	6.3	6.9	29	n.d.	6.6	6.1	＜5
35	8.2	7.8	6.1	6.3	29	n.d.	6.6	6.1	＜5
35	8.2	7.8	6.1	6.3	33	7.0	7.3	6.1	6.0
18	7.4	7.4	6.0	7.5	33	7.0	7.3	6.1	6.0
18	7.4	7.4	6.0	7.5	20	7.1	7.3	5.9	7.2
19	7.0	7.6	5.9	7.5	20	7.1	7.3	5.9	7.2
19	7.0	7.6	5.9	7.5	31	n.d.	7.56	5.9	6.0
37	n.d.	7.0	5.8	5.9	31	n.d.	7.56	5.9	6.0
37	n.d.	7.0	5.8	5.9	32	n.d.	7.3	5.7	7.4
6	7.4	7.4	5.6	5.7	32	n.d.	7.3	5.7	7.4
6	7.4	7.4	5.6	5.7	7	6.6	7.7	5.5	5.6
8	＜5	7.2	5.5	6.0	7	6.6	7.7	5.5	5.6
8	＜5	7.2	5.5	6.0	4	n.d.	6.8	5.4	6.2
34	6.8	6.5	5.4	5.6	4	n.d.	6.8	5.4	6.2
34	6.8	6.5	5.4	5.6	36	n.d.	6.2	5.2	5.3
14	7.1	6.6	＜6	6.3	36	n.d.	6.2	5.2	5.3

D. composition embodiment

" activeconstituents " that runs through these embodiment uses is (A.I.) relevant with compound, its pharmaceutically-acceptable acid addition, its stereochemistry heterogeneous forms or its N-oxide form according to formula (I).

Embodiment is D.1: oral liquid

4-methyl hydroxybenzoate (9g) and 4-nipasol (1g) are dissolved in the pure water (41) that boils.At first with 2,3-desoxalic acid (10g) and afterwards A.I (20g) being dissolved in 31 these solution.The lingering section of back one solution and last solution is merged, and to wherein adding 1,2,3-glycerol (12l) and sorbyl alcohol 70% solution (3l).Soluble saccharin (40g) is dissolved in the water (500ml), and adds raspberry (2ml) and gooseberry essence (2ml).Back one solution and last solution are merged, and adding an amount of water to volume is 201, provides each teaspoon (5ml) to contain the oral liquid of 5mg activeconstituents.Final solution is loaded in suitable containers.

Embodiment is D.2: film coating tablet

The preparation of tablet core

The mixture of thorough mixing A.I. (100g), lactose (570g) and starch (200g) uses the sodium lauryl sulphate (5g) in water (200ml) and the solution humidification of polyvinylpyrrolidone (10g) afterwards.Powdered mixture, dry and screening again that screening is moist.Then, add Microcrystalline Cellulose (100g) and hydrogenated vegetable oil (15g).The thorough mixing all the components, and be pressed into tablet, obtaining 10,000 tablets, each tablet contains the activeconstituents of 10mg.

Dressing

In methylcellulose gum (10g) solution in Denatured alcohol (75ml), be added on ethyl cellulose (5g) solution in the methylene dichloride (150ml).Then, add methylene dichloride (75ml) and 1,2,3-glycerol (2.5ml).Fusing polyoxyethylene glycol (10g) also is dissolved in it in methylene dichloride (75ml).Back one solution is added in the last solution, and add Magnesium Stearate then (2.5 g), polyvinylpyrrolidone (5g) and spissated colored suspension liquid (30ml), whole mixture is carried out homogenate.In coating device, use thus obtained mixture that the tablet core is carried out dressing.

Embodiment is D.3: injection liquid

4-methyl hydroxybenzoate (1.8g) and 4-nipasol (0.2g) are dissolved in the water for injection (500ml) that boils.Be cooled to after about 50 ℃, stir and add lactic acid (4g), propylene glycol (0.05g) and A.I. (4g) down.Solution is cooled to room temperature, and adds an amount of water for injection, obtain containing the solution of 4mg/ml A.I. to 1000ml.By filtering this solution is sterilized, and load in sterile chamber.

Claims

1. the compound of following formula (I), its N-oxide form, its pharmaceutically acceptable addition salt or its stereochemistry heterogeneous forms:

Wherein:

N equals 0,1,2,3,4,5 or 6 integer;

I, j are independently of each other for equaling 0,1,2,3 or 4 integer;

R equals 0,1,2,3 or 4 integer;

Wherein:

P equals 0,1,2,3 or 4 integer;

Q equals 1 or 2 integer;

M equals 0,1,2 or 3 integer;

Each R ³Be selected from halogen independently of each other, hydroxyl, cyano group, alkyl, alkoxyalkyl, aryloxyalkyl group, list or two (alkyl) aminoalkyl group, hydroxyl carbonylic alkyl, alkoxycarbonyl alkyl, list or two (alkyl) aminocarboxyl alkyl, single or two (aryl) aminocarboxyl alkyl, the single or amino carbonyl oxyalkyl of two (alkyl), the alkyl oxy carbonyl oxygen alkyl, fragrant amino carbonyl oxygen base alkyl, aryl alkyl amino carbonyl oxyalkyl, aryl, alkoxyl group, aryloxy, alkane carbonyl oxygen base, fragrant carbonyl oxygen base, aralkyl carbonyl oxygen base, alkyl carbonyl, aromatic carbonyl, aryloxy carbonyl, hydroxycarbonyl group, carbalkoxy, list or dialkyl amido, alkyl carbonyl amino, aromatic alkyl carbonyl amino, aromatic carbonyl amino, alkoxycarbonyl amino, amino carbonyl amino, single or two (aralkyl) amino carbonyl amino, alkane alkylsulfonyl alkyl amino-carbonyl amino; Or

Two R ³Group can form divalent group together:

-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-1)

-O-CR ⁵R ⁵-CR ⁵R ⁵- (b-2)

-O-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-3)

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵- (b-4)

-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-5)

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-6)

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵- (b-7)

-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O-(b-8) and

-O-CR ⁵R ⁵-CR ⁵R ⁵-CR ⁵R ⁵-O- (b-9)

Each R ¹⁰Be alkyl or cyano group independently of each other;

A and B are separately independently of each other for being fused to the aryl or the heteroaryl of center ring, and be selected from following group: furyl, thienyl, pyrryl,  azoles base, thiazolyl, imidazolyl, different  azoles base, isothiazolyl, the  di azoly, triazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indyl, the indolizine base, isoindolyl, benzofuryl, isobenzofuran-base, benzothienyl, indazolyl, benzimidazolyl-, benzothiazolyl, quinolizinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, chromenyl, naphthyridinyl, and naphthyl, condition is that at least one is one of above-mentioned heteroaryl among A and the B;

Y represent O, S, S (=O), S (=O) ₂Or NR ⁸

X represents CR ⁶R ⁷, O, S, S (=O), S (=O) ₂Or NR ⁸Wherein

Halogen is represented fluorine, chlorine, bromine and iodine.

2. according to the compound of claim 1, it is characterized in that: R ¹And R ²Be hydrogen or alkyl separately independently of each other, each alkyl group is optional to be replaced by hydroxyl, or R ¹And R ²Form formula (a-3) or group (a-5) with the nitrogen-atoms that connects them, wherein m equals 1 or 2 integer.

3. according to each compound of claim 1-2, it is characterized in that: A and B be separately independently of each other for aryl or be selected from thienyl and the heteroaryl groups of pyridyl, and condition is that among A and the B at least one is heteroaryl groups.

4. according to the compound of claim 3, it is characterized in that: A is an aryl, B be wherein S at 9 or 11 thienyl.

5. according to the compound of claim 4, it is characterized in that: X is S.

6. according to each compound of claim 1-5, it is characterized in that: Y is O.

7. according to each compound of claim 1-6, it is characterized in that: Y is CR ⁶R ⁷, O, S, S (=O), S (=O) ₂Or NR ⁸

8. according to each compound of claim 1-7, it is characterized in that:

N equals 1 integer;

I equals 0 integer;

J equals 0 or 1 integer;

R equals 0 integer;

A is a phenyl;

B is thienyl or pyridyl;

R ⁹Be hydrogen;

R ¹⁰Be hydrogen, methylol, methoxycarbonyl or ethoxycarbonyl;

Y is O;

X is CH ₂, S or N-benzyl.

9. according to each compound of claim 1-8, as medicine.

10. pharmaceutical composition, it contains pharmaceutically acceptable carrier or thinner, and as the treatment significant quantity of activeconstituents according to each compound of claim 1-9.

11. be used to prepare the purposes of medicine according to each compound of claim 1-9, wherein said medicine is used to prevent and/or treat and passes through 5HT ₂Acceptor is 5HT particularly _2AAnd 5HT _2CAcceptor and D ₂Receptor-mediated illness and the illness that suppresses mediation by norepinephrine reuptake.

12. be used to prepare the purposes that is used for the treatment of and/or prevents the medicine of following central nervous system disorders according to each compound of claim 1-9: anxiety, depression and mild depression, bipolar disorder, sleep and sexual dysfunction, psychosis, marginal psychosis, schizophrenia, migraine, personality disorder, obsessive compulsive disorder, social phobia, panic attack, attention disorders, organic mental disorders, the children ' s spirit obstacle is attacked, particularly dysmnesia among the elderly and posture obstacle, habituation, obesity, Bulimia nerovsa, and similar conditions.

13. be used to prepare the purposes that is used for the treatment of and/or prevents the medicine of following illness according to each compound of claim 1-9: the habituation character of anxiety, psychosis, depression, the bipolar disorder that comprises the two-phase depression, migraine and drug abuse.

14. the preparation method according to the compound of formula (I) is characterized in that: randomly in the presence of suitable alkali, use formula HNR in the reaction-inert solvent neutralization ¹R ²Amine the intermediate of formula (II) is carried out the N-alkylation, wherein, R ⁹, i, j, ring A, ring B and X all have defined implication in the formula (I), and wherein W represents suitable leavings group, wherein at formula HNR ¹R ²In, R ¹And R ²Suc as formula defining in (I);

And, if desired, can transform mutually according to the compound of method for transformation known in the art formula (I), and, in addition, if desired, by using acid treatment that the compound of formula (I) is converted into the non-toxicity acid salt of therapeutic activity, or the compound of formula (I) is converted into the non-toxic bases additive salt of therapeutic activity by the use alkaline purification, or conversely, by the acid salt form being converted into free alkali with alkaline purification, or by with acid treatment base addition salt being converted into free acid; And, if desired, prepare its stereochemistry heterogeneous forms, its N-oxide compound and quaternary ammonium salt thereof.